Laureate Professor Paul Foster is a leader and a visionary keen on making life easier for patients suffering from respiratory disorders. As Director, he coordinates investigative efforts for a variety of prominent, preclinical research groups in the Hunter, seeking to solidify links between disease state, infections, inflammation and immune responses.

"Our focus is on identifying the molecular and cellular pathways that cause these conditions," he explains.

"It's a really fundamental approach – we're looking at the hows and whys at a cellular level."

"For example, we've established several transgenic mouse models to gain insights into new approaches to diagnosis and treatment."

Paul is the Director of the University of Newcastle's Priority Research Centre for Asthma and Respiratory Diseases, the Director of VIVA (Vaccines, Immunology, Viruses and Asthma) at the Hunter Medical Research Institute, and the University's Chair in Immunology. He also teaches into the second and third-year immunology programs in the School of Biomedical Sciences and Pharmacy.

"I'm not physically involved in experimentation anymore," he concedes.

"I hold group meetings to help analyse the data that comes in on specific projects."

"It's nice to be able to contribute to the generation of knowledge that underpins really important work."

"Our aim is to unravel the complexities of the pathophysiology of various chronic airway diseases."

Further afield, Paul has contributed significantly to the global advancement of respiratory medicine, bringing together clinical, applied, epidemiological and basic science research to examine problems associated with asthma, emphysema and respiratory infections. His Centres' discoveries, made by senior scientists, postdoctoral fellows, PhD candidates and eager undergraduates, have similarly informed the development of new therapeutic strategies and the translation of basic work to clinical outcomes.

All muscle

Paul began his research career with a first class Honours Degree in pharmacology and biochemistry from the University of Western Australia. Looking at smooth muscle functioning in asthma, he sought to understand the role of this cell in asthma.

"Smooth muscle lines the walls of blood vessels and our airways, and controls the diameter of these structures," Paul states.

"In asthma airway, smooth muscle constricts and narrows the breathing tube, leading to limitation in airflow."

Awarded a Commonwealth Scholarship after receiving his Honours Degree in 1983, he moved across the country to undertake a PhD at the Australian National University's John Curtin School of Medical Research. Exploring the biochemical basis of the skeletal muscle disorder known as malignant hyperpyrexia during the four-years of investigation, Paul described a number of molecular defects that predispose to this often-fatal illness, which is triggered by general anaesthesia.

"Calcium regulation is abnormal within the muscle cells and this mechanism is very sensitive to general anaesthetics," he clarifies.

"When an anaesthetic hits the muscle, it causes a release of lots of calcium and a series of uncontrollable rigor contractions, which make the body very hot."

"Malignant hyperpyrexia is a skeletal muscle abnormality which when triggered, leads to loss of core metabolic control and cardiac arrest."

Paul continued to study the development of this disease post-PhD, staying on at the prestigious medical school to accept several postdoctoral fellowships. Related to a burgeoning interest in calcium movement within airway cells and muscle cells, the extension widened the research scope of a once "very specific and narrow" muscle biochemistry field.

"John Curtin also offered me a professorial position," he discloses.

"The place produced two Nobel Prize winners and was research intensive, so it was exciting to be there."

Life and breath

Paul found a new avenue of investigation once the molecular defects in malignant hyperpyrexia were found and "fully characterised," opting to return to his primary interest in asthma in the late 1990s.

"We started to examine inflammation, which is the abnormal accumulation of white blood cells in the lung that drives asthmatic responses and other lung conditions," he states.

"I was still very interested in that area of research."

Paul then moved to the University of Newcastle in 2002, establishing the Priority Research Centre for Asthma and Respiratory Diseases. Internationally recognised for its talented clinician scientists and doctors, as well as an extensive publication catalogue, the Centre is a national training hub for respiratory medicine and immunology.

"We work on understanding how chronic airway conditions progress," he declares.

"We also look closely at the role of infection in driving pathogenesis."

Fundamental and experimental

Current research in Paul's laboratory is aimed at defining the cellular and molecular processes that underlie the development of allergic disease and viral-induced pulmonary inflammation. Another major objective is to gather a concrete understanding of the role of non-coding RNA in the regulation of blood cell development.

"Messenger RNAs produce proteins," he discloses.

"Non-coding RNAs, however, don't code for proteins, and their function is just beginning to be understood."

"We know they can regulate transcriptional networks within cells and therefore profoundly affect the functioning of organs."

"We're trying to figure out why microRNA and non-coding RNA are important in asthma as this will hopefully allow us to identify and create new therapeutic targets."

Paul and his team are simultaneously exploring the role of T-lymphocytes in the onset and progression of several lung disorders.

"These are small cells that can be activated in a very specific manner by specific antigens," he reveals.

"When they are activated appropriately, their job is to kill infectious agents."

"When they are actively inappropriately, they damage tissue and this over time leads to chronic disease."

Pointing to the latter as an all-too-common occurrence in the cells of patients with asthma and emphysema, Paul is seeking to make sense of a complicated disease process. He's breaking T-lymphocytes down into subsets for further study, hoping to harness knowledge about their individual roles in allergic responses and inflammatory conditions of the lung.

"We're really interested in the T-helper 2 subset," Paul shares.

"We also recently described the role of generation of a new T-helper 22 subset."

"We now know how to generate that cell that will allow its characterisation."

At the same time, the respiratory researcher is supervising PhD students working on models of severe asthma.

"This particular condition is very difficult to treat," he acknowledges.

"You get given steroids and bronchodilators but often in these patients they're not very effective – and no one knows why."

"Infection also plays a critical role triggering acute exacerbations of asthma."

Paul's team is developing a number of experimental mouse models to investigate, and manipulate, the hallmark features of asthma and other respiratory diseases, and they are looking to classify its key pathogenic events and explore the role of associated infections in disease processes.

From the bench to the bedside

Paul is a fan of collaborative thinking both in and out of the laboratory. He is also a firm believer in the power of translational research.

"What all of us want to see is a better outcome for patients," the research leader says.

Joining forces to ease the wheeze

From the bench to the bedside, the University of Newcastle's Priority Research Centre for Asthma and Respiratory Diseases is leading the way in the understanding, management and treatment of chronic airway conditions.

The work of the Centre is internationally recognised, having contributed significantly to advancing both medical practice and policy through its discoveries.

Its studies are regularly published in the most prestigious journals and it is a major training hub for respiratory medicine and immunology, attracting gifted PhD students and postdoctoral researchers from around the world to work and study in Newcastle.

Foster and Gibson's teams work under the umbrella of the Hunter Medical Research Institute (HMRI), a partnership between the University of Newcastle and Hunter New England Health. They also collaborate with research groups in Sydney, Newcastle, Melbourne and Perth as part of the Cooperative Research Centre for Asthma and Airways, a $55 million government-backed program.

Gibson is working at the clinical interface, using his role as a respiratory physician at the John Hunter Hospital in Newcastle to inform his research into treatments and management strategies for asthma and airway disease.

Foster, the University's Chair in Immunology, investigates the molecular and cellular mechanisms of disease in the laboratory. Both have a keen interest in unravelling the critical role of inflammation in asthma and other respiratory conditions.

"We are constantly on the lookout for better treatments but with a disease like asthma, management is also important," Gibson says.

"For some people, just understanding what is happening to them is enough to make a big difference to their condition and quality of life."

Gibson's clinically based team is involved in research projects with significant implications for future treatment and management of airway disease (see below).

Novel discoveries have also been made by the centre's laboratory-based researchers. These discoveries have enhanced the understanding of processes associated with the development and progression of respiratory diseases.

Centre scientists study the cellular and molecular functions of the diseases on animal models then collaborate with the clinical researchers to validate their findings using human tissue.

Foster says the centre is at the forefront of interpreting how inflammation, which underpins airway disease, occurs and of developing new anti-inflammatory treatments.

A major breakthrough was their research into how microRNA molecules, which regulate protein production in human cells, can cause inflammation in the body that can manifest as asthma. Working out how to control that inflammatory response has provided scientists with a therapeutic target, which could lead to new treatments.

"Steroids are the conventional treatment, but they can have side effects and while they dampen response, they do not cure the disease," Foster explains.

"Also, not everyone is responsive to steroids and within that non-responsive group there is a lot of morbidity."

Foster says his team has made a significant contribution to the understanding of the mechanisms of steroid-resistant inflammatory pathways that may be relevant to asthma, bringing them closer to the goal of developing alternative treatments. Other critical areas of laboratory research focus on allergies, viruses and infection as triggers for asthma.

While the two arms of research within the centre are undertaken by different teams, Foster says it is the critical mass that contributes to its overall success.

"What we have is diversity and common interest," he says. "There are similar centres of excellence around the world but they primarily do either clinical-based research or basic immunology. The way the two are integrated here is what makes us unique and underpins our success."

"People are willing to collaborate," Gibson agrees, "and it is only by linking patient-focused research with laboratory discoveries and evidence-based medicine that we are able to get these broad insights into disease."

Leading the way

Professor Peter Gibson's clinical research team is leading three groundbreaking projects that could revolutionise the treatment of asthma.

These specific projects involve better management of asthma in pregnancy, the development of a blood test to diagnose the disease and the treatment of non-eosinophilic asthma with macrolide antibiotics.

The team's study into asthma in pregnancy was prompted by the reluctance of women to use treatments during gestation, even though severe asthmatic episodes can be harmful to both mother and child.

As part of this project, researchers measured nitric oxide, which is produced by inflamed airways, in the pregnant patient's exhaled breath. They were then able to adjust the amount of medication according to the severity of the inflammation.

In many cases this reduced the amount of steroid that needed to be administered, which made women more likely to take their medication as they were less apprehensive about the treatment and its effects on their unborn child.

Another benefit was that the frequency of asthma exacerbations, or episodes, decreased because the condition was being better managed.

In another study, published this year in the American Journal of Respiratory and Critical Care Medicine, the team used the emerging scientific field of proteomics (the study of proteins) to identify four blood-based biomarkers that when analysed together can distinguish between asthma and chronic obstructive pulmonary disease.

The two diseases share common symptoms, so are difficult to distinguish, but require different therapeutic approaches.

This finding could lead to the development of the first blood test for asthma, which would be a major diagnostic breakthrough.

The third project is the AMAZES study (Asthma and Macrolides: Azithromycin Efficacy and Safety). It will trial an alternative treatment, known as a macrolide antibiotic, for asthma that is not responsive to conventional steroid medication.

Steroids treat a particular cell, called an eosinophil, which is thought to provoke inflammation when present in increased levels. But research has established that up to half of adults with asthma symptoms have normal levels of eosinophils and respond poorly to conventional treatment.

The five-year, $2.9 million study is trialling the antibiotic on approximately 400 asthmatics in four cities and is the biggest study into non-eosinophilic asthma in the world. It is funded by the National Health and Medical Research Council.

Career Summary

Biography

Professor Paul Foster is the Director of the Priority Research Centre for Healthy Lungs; the Virus, Infection/Immunity, Vaccines and Asthma Program, Hunter Medical Research Institute and the Cooperative Research Centre (CRC) for Asthma and Airways (Newcastle node). He also currently holds the Chair of Immunology, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle. He is also a visiting Professor at Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

He serves as an Associate Editor of the American Journal of Respiratory Cell and Molecular Biology and the Journal of Pharmacology and Therapeutics, and is on the Editorial Boards of a number of leading international immunology/allergy journals. Professor Foster's research focuses on understanding the molecular and cellular basis of asthma, allergy, respiratory disorders, and chronic inflammation.

His research program focuses on translational approaches directed towards the development of novel anti-inflammatory therapies. Professor Foster's research findings are published in the most highly ranked medical and biomedical science journals (e.g. Nature Immunology and Journal of Experimental Medicine). Essential Science Indicators metrics places his team on the forefront of his field internationally. Professor Foster receives numerous and ongoing invitations to speak and chair sessions and leading international conferences in immunology and respiratory medicine (e.g. American Academy of Asthma, Allergy and Immunology, Keystone, Cold Spring Harbor, International Congress on Immunology and International Eosinophil meeting).

The importance of his team's work has been recognised through award of over $10.5 million in direct funding (since 2003) through Australian national competitive grants. Since 1995 Professor Foster's laboratory has focused on the biology of T cells and granulocytes, and on signaling by cytokines and chemokines pertinent to regulating allergic inflammatory responses, in particular asthma.

In the last 5 years we have extended our focus to understanding the relationship between inflammation induced by infection (viruses, bacteria and microbial products), at various times through life, on the subsequent development of the T cell repertoire and on chronic inflammation in the lung. A focus on the role of microRNAs in the regulation of inflammation is also a main focus. Professor Foster's activities have been supported through grants from the NHMRC (program and project grants), Australian Research Council (Discovery and LIEF grants), Human Frontiers Science Foundation, and through the CRC for Asthma and Airways. Professor Foster actively contributes to peer review at a national and international level (e.g. NHMRC; fellowship, program and project reviews/grant panel; Wellcome Trust; and leading international journals (e.g. J. of Clin. Invest., J. of Exp. Med., and Nature).

Research ExpertiseCurrent research in my laboratory primarily aims at defining the key cellular and molecular processes that underlie the development of allergic disease (lung, skin and gastrointestinal tract) and of viral (RSV and influenza) induced pulmonary inflammation. We are particularly interested in the molecular events that predispose to remodeling of the airways in chronic disease and the subsequent impact on lung function. In particular, projects are focusing on the biology of CD4+ Th2 cells, CD8+ T cells and eosinophils, and in signaling arrangements between cytokine and chemokine systems that pertain to allergic disease, viral induced pathogenesis and viral induced exacerbation of asthma.

Our aim is to develop integrative concepts on molecular mechanisms of pathogenesis by employing an approach that is multifactorial ranging from transgenic systems to the identification of novel gene products. The laboratory has established in vivo models of asthma (acute and chronic), allergic cutaneous disease and of eosinophil and lymphocyte homing to sites of allergen or viral provocation.

Models of RSV infection in the presence and absence of allergic inflammation are also established. These models, in conjunction with mice that are factor deficient or transgenic (constitutive and inducible systems that are airway specific, and T cell transgenic systems), are currently being employed to define the individual role of inflammatory cells and cytokines/chemokines in the pathophysiology of allergic and viral disorders and viral induced exacerbation of allergic inflammation. Collectively, this approach is providing a fundamental platform for the identification of key targets for potential therapeutic intervention in these diseased states and models for the development of novel anti-inflammatory approaches. Models of leukocyte trafficking and pathogenesis are combined with experimental programs at a cellular level to enhance the understanding of the molecular basis of disease. Novel mechanisms to attenuate allergic and viral induced disease are also being explored. We have also established models of chronic obstructive pulmonary disease (COPD).

Current PhD and Honours projects within my team aim to gather an understanding in:• the role of miRNA in asthma and infection • the role of viruses in inducing asthma and COPD • miRNA regulation of leukocyte differentiation• the innate immune system in severe asthma

Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-Type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL + CD11b + monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associ... [more]

Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associated alterations in expression with putative mRNA targets that are critical during differentiation of macrophages. In an effort to map the dynamic changes in the bone marrow (BM), we profiled whole BM cultures during differentiation into macrophages. We identified 112 miRNAs with expression patterns that were differentially regulated 5-fold or more during BMDM development. With TargetScan and MeSH databases, we identified 1267 transcripts involved in 30 canonical pathways linked to macrophage biology as potentially regulated by these specific 112 miRNAs. Furthermore, by employing miRanda and Ingenuity Pathways Analysis (IPA) analysis systems, we identified 18 miRNAs that are temporally linked to the expression of CSF1R, CD36, MSR1 and SCARB1; 7 miRNAs linked to the regulation of the transcription factors RUNX1 and PU.1, and 14 miRNAs target the nuclear receptor PPARa and PPARÂ¿. This novel information provides an important reference resource for further study of the functional links between miRNAs and their target mRNAs for the regulation of differentiation and function of macrophages.

Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acety... [more]

Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyperresponsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma.

Mattes J, Collison AM, Plank MW, Phipps S, Foster PS, 'Antagonism of microRNA-126 suppresses the effector function of T(H)2 cells and the development of allergic airways disease', Proceedings of the National Academy of Sciences of the United States of America, 106 18704-18709 (2009) [C1]

Background-Ischemia/reperfusion (I/R) injury complicates myocardial infarction and stroke by exacerbating tissue damage and increasing risk of mortality. We have recently identified C-type natriuretic peptide (CNP) as an endothelium-derived hyperpolarizing factor in the mesenteric resistance vasculature and described a novel signaling pathway involving activation of natriuretic peptide receptor C (NPR-C), which plays a pivotal role in the regulation of local blood flow. We tested the hypothesis that CNP/NPR-C signaling is a novel regulatory pathway governing coronary blood flow and protecting against I/R injury. Methods and Results-CNP and (Cys18)-atrial natriuretic factor (4-23) amide (cANF 4-23 ) elicited dose-dependent decreases in coronary perfusion pressure (CPP) that were blocked by Ba 2+ and ouabain in the isolated Langendorff rat heart. The endothelium-dependent vasodilator acetylcholine elicited the release of CNP from the coronary endothelium. CNP and cANF 4-23 reduced infarct size after 25 minutes of global ischemia and 120 minutes of reperfusion, maintaining CPP and left ventricular pressure at preischemic values. The vasorelaxant and protective activity of CNP and cANF 4-23 were enhanced in the absence of endothelium-derived nitric oxide. Conclusion-Endothelium-derived CNP is involved in the regulation of the coronary circulation, and NPR-C activation underlies the vasorelaxant activity of this peptide. Moreover, this newly defined pathway represents a protective mechanism against I/R injury and a novel target for therapeutic intervention in ischemic cardiovascular disorders.

Nitric oxide (NO) production by the vascular endothelium maintains an essential antiinflammatory, cytoprotective influence on the blood vessel wall. A key component of this activi... [more]

Nitric oxide (NO) production by the vascular endothelium maintains an essential antiinflammatory, cytoprotective influence on the blood vessel wall. A key component of this activity is attributed to prevention of leukocyte-endothelial cell interactions, yet the underlying mechanisms remain unclear. The NO receptor, soluble guanylate cyclase (sGC), is expressed in endothelial cells but fulfils an unknown function. Therefore, we used intravital microscopy in mesenteric postcapillary venules from WT and endothelial nitric oxide synthase (eNOS) knockout (eNOS -/- ) mice, and an sGC activator (BAY 41-2272), to investigate a potential role for sGC in the regulation of adhesion molecule expression and leukocyte recruitment. Leukocyte rolling and adhesion was 6-fold greater in eNOS -/- than WT animals. BAY 41-2272 and the NO-donor, diethylamine-NONOate, reduced leukocyte rolling and adhesion in eNOS -/- mice to levels observed in WT animals. These effects were blocked by the sGC inhibitor ODQ [1 H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one], which itself caused a 6-fold increase in leukocyte rolling and adhesion in WT mice. Increased leukocyte rolling and adhesion in IL-1Ã-treated mice was also inhibited by BAY 41-2272. Fluorescence-activated cell sorting analysis in vitro and a specific P-selectin neutralizing antibody in vivo revealed that selective down-regulation of P-selectin expression accounted for the anti-adhesive effects of sGC activation. These data demonstrate that sGC plays a key antiinflammatory role by inhibiting P-selectin expression and leukocyte recruitment.

Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma... [more]

Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4 + T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4 + T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulin- synthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4 + T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target.

Hogan S, Foster PS, Charlton B, Slattery R, 'Prevention of Th2-mediated murine allergic airways disease by soluble antigen administration in the neonate', Proceedings of the National Academy of Sciences of the United States of America, . (1998) [E1]

Research Collaborations

The map is a representation of a researchers co-authorship with collaborators across the globe. The map displays the number of publications against a country, where there is at least one co-author based in that country. Data is sourced from the University of Newcastle research publication management system (NURO) and may not fully represent the authors complete body of work.

Laureate Professor Paul Foster has been awarded a Doctor of Science degree (D.Sc.) from the Australian National University at a ceremony on Friday July 13th, 2012. This is a particularly prestigious award given the Australian National University is ranked

Laureate Professor Paul Foster

Position

Laureate ProfessorSchool of Biomedical Sciences and PharmacyFaculty of Health and Medicine

Laureate Professor Paul Foster has been awarded a Doctor of Science degree (D.Sc.) from the Australian National University at a ceremony on Friday July 13th, 2012. This is a particularly prestigious award given the Australian National University is ranked